Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment.

Alzheimer's disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the APP and secretase location relative to ordered or disordered membrane microdomains. We used high-resolution NMR to probe the interactions of the cholesterol analog with APP transmembrane domain in two membrane-mimicking systems resembling ordered or perturbed lipid environments (bicelles/micelles).

Systematic evaluation of intratumoral and peripheral BCR repertoires in three cancers.

The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers.

From Structure to Function: Analysis of the First Monomeric Pyridoxal-5'-Phosphate-Dependent Transaminase from the Bacterium .

The first monomeric pyridoxal-5'-phosphate (PLP)-dependent transaminase from a marine, aromatic-compound-degrading, sulfate-reducing bacterium Tol2, has been studied using structural, kinetic, and spectral methods. The monomeric organization of the transaminase was confirmed by both gel filtration and crystallography. The PLP-dependent transaminase is of the fold type IV and deaminates D-alanine and ()-phenylethylamine in half-reactions.

Targeted macrophage mannose receptor (CD206)-specific protein delivery via engineered extracellular vesicles.

Extracellular vesicles (EVs) show great potential for therapeutic delivery to human cells, with a focus on modulating immune responses. The most promising targets for inducing humoral and cellular immunity against a specific antigen are macrophages (Mϕs) and dendritic cells (DCs). Targeting mannose receptors (CD206), which are highly expressed on these antigen-presenting cells, to promote the presentation of specific antigens through EV-mediated uptake, is a promising strategy in clinical immunotherapy.

Core-Shell Chitosan Particles Targeting Membrane-Bound Heat Shock Protein 70 for Cancer Therapy.

Anti-cancer targeted therapy is a promising approach. However, the identification of target molecules over-expressed in a wide range of tumors remains a significant challenge. The aim of this study was to analyze the expression of cell membrane-exposed heat shock protein 70 kDa (mHSP70) on different tumor cells and to develop a nanoscale delivery system based on a monoclonal antibody (mAb) that recognizes mHSP70 and uses chitosan core-shell nanoparticles (NPs).

On the Properties of Styrene-Maleic Acid Copolymer-Lipid Nanoparticles: A Solution NMR Perspective.

The production of functionally active membrane proteins (MPs) in an adequate membrane environment is a key step in structural biology. Polymer-lipid particles based on styrene and maleic acid (SMA) represent a promising type of membrane mimic, as they can extract properly folded MPs directly from their native lipid environment. However, the original SMA polymer is sensitive to acidic pH levels, which has led to the development of several modifications: SMA-EA, SMA-QA, and others.

Enhancing glioma treatment with 3D scaffolds laden with upconversion nanoparticles and temozolomide in orthotopic mouse model.

Targeted drug delivery for primary brain tumors, particularly gliomas, is currently a promising approach to reduce patient relapse rates. The use of substitutable scaffolds, which enable the sustained release of clinically relevant doses of anticancer medications, offers the potential to decrease the toxic burden on the patient's organism while also enhancing their quality of life and overall survival. Upconversion nanoparticles (UCNPs) are being actively explored as promising agents for detection and monitoring of tumor growth, and as therapeutic agents that can provide isolated therapeutic effects and enhance standard chemotherapy.

Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses.

Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation.

Two-dimensional high-throughput on-cell screening of immunoglobulins against broad antigen repertoires.

Identifying high-affinity antibodies in human serum is challenging due to extremely low number of circulating B cells specific to the desired antigens. Delays caused by a lack of information on the immunogenic proteins of viral origin hamper the development of therapeutic antibodies. We propose an efficient approach allowing for enrichment of high-affinity antibodies against pathogen proteins with simultaneous epitope mapping, even in the absence of structural information about the pathogenic immunogens.

α-Latrotoxin Tetramers Spontaneously Form Two-Dimensional Crystals in Solution and Coordinated Multi-Pore Assemblies in Biological Membranes.

α-Latrotoxin (α-LTX) was found to form two-dimensional (2D) monolayer arrays in solution at relatively low concentrations (0.1 mg/mL), with the toxin tetramer constituting a unit cell. The crystals were imaged using cryogenic electron microscopy (cryoEM), and image analysis yielded a ~12 Å projection map.

Correction: Yagolovich et al. DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma. 2022, , 12687.

In the original publication [...

Local Enrichment with Convergence of Enriched T-Cell Clones Are Hallmarks of Effective Peptide Vaccination against B16 Melanoma.

Background: Some peptide anticancer vaccines elicit a strong T-cell memory response but fail to suppress tumor growth. To gain insight into tumor resistance, we compared two peptide vaccines, p20 and p30, against B16 melanoma, with both exhibiting good in vitro T-cell responses but different tumor suppression abilities.

Methods: We compared activation markers and repertoires of T-lymphocytes from tumor-draining (dLN) and non-draining (ndLN) lymph nodes for the two peptide vaccines.

Intracellular and Extracellular Peptidomes of the Model Plant, Physcomitrium patens.

Here, we report our approach to peptidomic analysis of the plant model Physcomitrium patens. Intracellular and extracellular peptides were extracted under conditions preventing proteolytic digestion by endogenous proteases. The extracts were fractionated on size exclusion columns to isolate intracellular peptides and on reversed-phase cartridges to isolate extracellular peptides, with the isolated peptides subjected to LC-MS/MS analysis.

B cell clonality in cancer.

Carcinogenesis in the process of long-term co-evolution of tumor cells and immune environment essentially becomes possible due to incorrect decisions made, remembered, and reproduced by the immune system at the level of clonal populations of antigen-specific T- and B-lymphocytes. Tumor-immunity interaction determines the nature of such errors and, consequently, delineates the possible ways of successful immunotherapeutic intervention. It is generally recognized that tumor-infiltrating B cells (TIL-B) can play both pro-tumor and anti-tumor roles.

New Biocides Based on -Alkylcytidines: Effects on Microorganisms and Application for the Protection of Cultural Heritage Objects of Painting.

The rapid increase in the antibiotic resistance of microorganisms, capable of causing diseases in humans as destroying cultural heritage sites, is a great challenge for modern science. In this regard, it is necessary to develop fundamentally novel and highly active compounds. In this study, a series of -alkylcytidines, including 5- and 6-methylcytidine derivatives, with extended alkyl substituents, were obtained in order to develop a new generation of antibacterial and antifungal biocides based on nucleoside derivatives.

Extraribosomal Functions of Bacterial Ribosomal Proteins-An Update, 2023.

Ribosomal proteins (r-proteins) are abundant, highly conserved, and multifaceted cellular proteins in all domains of life. Most r-proteins have RNA-binding properties and can form protein-protein contacts. Bacterial r-proteins govern the co-transcriptional rRNA folding during ribosome assembly and participate in the formation of the ribosome functional sites, such as the mRNA-binding site, tRNA-binding sites, the peptidyl transferase center, and the protein exit tunnel.

Human RPF1 and ESF1 in Pre-rRNA Processing and the Assembly of Pre-Ribosomal Particles: A Functional Study.

Ribosome biogenesis is essential for the functioning of living cells. In higher eukaryotes, this multistep process is tightly controlled and involves a variety of specialized proteins and RNAs. This pool of so-called ribosome biogenesis factors includes diverse proteins with enzymatic and structural functions.

Toolkit for mapping the clonal landscape of tumor-infiltrating B cells.

Our current understanding of whether B cell involvement in the tumor microenvironment benefits the patient or the tumor - in distinct cancers, subcohorts and individual patients - is quite limited. Both statements are probably true in most cases: certain clonal B cell populations contribute to the antitumor response, while others steer the immune response away from the desired mechanics. To step up to a new level of understanding and managing B cell behaviors in the tumor microenvironment, we need to rationally discern these roles, which are cumulatively defined by B cell clonal functional programs, specificities of their B cell receptors, specificities and isotypes of the antibodies they produce, and their spatial interactions within the tumor environment.

Challenges in characterization of transcriptomes of extracellular vesicles and non-vesicular extracellular RNA carriers.

Since its original discovery over a decade ago, extracellular RNA (exRNA) has been found in all biological fluids. Furthermore, extracellular microRNA has been shown to be involved in communication between various cell types. Importantly, the exRNA is protected from RNases degradation by certain carriers including membrane vesicles and non-vesicular protein nanoparticles.

Influence of Amino Acid Substitutions in ApoMb on Different Stages of Unfolding of Amyloids.

To date, most research on amyloid aggregation has focused on describing the structure of amyloids and the kinetics of their formation, while the conformational stability of fibrils remains insufficiently explored. The aim of this work was to investigate the effect of amino acid substitutions on the stability of apomyoglobin (ApoMb) amyloids. A study of the amyloid unfolding of ApoMb and its six mutant variants by urea has been carried out.

Venom-gland transcriptomics and venom proteomics of the Tibellus oblongus spider.

The Tibellus oblongus spider is an active hunter that does not spin webs and remains highly underinvestigated in terms of the venom composition. Here, we describe venom glands transcriptome and venom proteome analysis for unveiling the polypeptide composition of Tibellus oblongus spider venom. The resulting EST database includes 1733 records, including 1263 nucleotide sequences with ORFs, of these 942 have been identified as toxin-coding.

Dual targeting of DR5 and VEGFR2 molecular pathways by multivalent fusion protein significantly suppresses tumor growth and angiogenesis.

Destroying tumor vasculature is a relevant therapeutic strategy due to its involvement in tumor progression. However, adaptive resistance to approved antiangiogenic drugs targeting VEGF/VEGFR pathway requires the recruitment of additional targets. In this aspect, targeting TRAIL pathway is promising as it is an important component of the immune system involved in tumor immunosurveillance.

Overexpression of KCNN4 channels in principal neurons produces an anti-seizure effect without reducing their coding ability.

Gene therapy offers a potential alternative to the surgical treatment of epilepsy, which affects millions of people and is pharmacoresistant in ~30% of cases. Aimed at reducing the excitability of principal neurons, the engineered expression of K channels has been proposed as a treatment due to the outstanding ability of K channels to hyperpolarize neurons. However, the effects of K channel overexpression on cell physiology remain to be investigated.

Design and preparation of pH-sensitive cytotoxic liposomal formulations containing antitumor colchicine analogues for target release.

Herein, we describe the synthesis of pH-sensitive lipophilic colchicine prodrugs for liposomal bilayer inclusion, as well as preparation and characterization of presumably stealth PEGylated liposomes with above-mentioned prodrugs. These formulations liberate strongly cytotoxic colchicinoid derivatives selectively under slightly acidic tumor-associated conditions, ensuring tumor-targeted delivery of the compounds. The design of the prodrugs is addressed to pH-triggered release of active compounds in the slight acidic media, that corresponds to tumor microenvironment, while keeping sufficient stability of the whole formulation at physiological pH.

Selective targeting of α7 nicotinic acetylcholine receptor by synthetic peptide mimicking loop I of human SLURP-1 provides efficient and prolonged therapy of epidermoid carcinoma .

α7-Type nicotinic acetylcholine receptor (α7-nAChR) promotes the growth and metastasis of solid tumors. Secreted Ly6/uPAR-Related Protein 1 (SLURP-1) is a specific negative modulator of α7-nAChR produced by epithelial cells. Here, we investigated mechanisms of antiproliferative activity of recombinant SLURP-1 in epidermoid carcinoma A431 cells and activity of SLURP-1 and synthetic 21 a.